RFFL (ring finger and FYVE like domain containing E3 ubiquitin protein ligase) is an endosome-associated E3 ubiquitin ligase that regulates diverse cellular processes through ubiquitin-mediated protein degradation 1. The protein functions as a critical regulator of protein quality control and cellular homeostasis by targeting multiple substrates for proteasomal degradation. RFFL ubiquitinates and degrades the cardiac potassium channel hERG through the ER-associated degradation pathway, thereby regulating cardiac repolarization 2. The ligase also targets mitofusin 2 (MFN2) for ubiquitination, controlling mitochondrial morphology and preventing hyperfused mitochondria 3. Additional validated substrates include JMJD6 and DNAJB11, identified through comprehensive proteomic analysis 4. RFFL plays important roles in endocytic recycling by ubiquitinating Rab11 effectors including EHD1, MICALL1, and Rab11-FIPs, regulating endocytic recycling compartment function 1. In disease contexts, RFFL acts as an oncogenic factor by promoting p53 degradation and is negatively regulated by tumor suppressor miR-133a in colorectal cancer 5. The protein also stabilizes DHX9 by preventing its degradation, promoting breast cancer progression through PI3K/AKT signaling 6. RFFL represents a promising therapeutic target for both cancer treatment and cystic fibrosis, as α-tocopherol succinate can inhibit RFFL-substrate interactions 7.